Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells

Cardiosphere-derived cells (CDCs) are an attractive cell type for tissue regeneration, and autologous CDCs are being tested clinically. However, autologous therapy necessitates patient-specific tissue harvesting and cell processing, with delays to therapy and possible variations in cell potency. The use of allogeneic CDCs, if safe and effective, would obviate such limitations. We compared syngeneic and allogeneic CDC transplantation in rats from immunologically-mismatched inbred strains.

Stricture prevention after extended circumferential endoscopic mucosal resection by injecting autologous keratinocytes in the sheep esophagus

During the past decades, endoscopic mucosal resection (EMR) has been developed to treat early intramucosal esophageal cancers and dysplastic Barrett's esophagus. The primary drawback of this method is severe postsurgical esophageal stricture formation. The purpose of this preclinical study was to assess strategies for prevention of this major complication by injecting autologous keratinocytes in the EMR mucosal defect in the sheep model.

Cardiac transplantation with hearts from donors after circulatory declaration of death: haemodynamic and biochemical parameters at procurement predict recovery following cardioplegic storage in a rat model

OBJECTIVES: Donation after circulatory declaration of death (DCDD) could significantly improve the number of cardiac grafts for transplantation. Graft evaluation is particularly important in the setting of DCDD given that conditions of cardio-circulatory arrest and warm ischaemia differ, leading to variable tissue injury. The aim of this study was to identify, at the time of heart procurement, means to predict contractile recovery following cardioplegic storage and reperfusion using an isolated rat heart model. Identification of reliable approaches to evaluate cardiac grafts is key in the development of protocols for heart transplantation with DCDD. METHODS: Hearts isolated from anaesthetized male Wistar rats (n = 34) were exposed to various perfusion protocols. To simulate DCDD conditions, rats were exsanguinated and maintained at 37°C for 15-25 min (warm ischaemia). Isolated hearts were perfused with modified Krebs-Henseleit buffer for 10 min (unloaded), arrested with cardioplegia, stored for 3 h at 4°C and then reperfused for 120 min (unloaded for 60 min, then loaded for 60 min). Left ventricular (LV) function was assessed using an intraventricular micro-tip pressure catheter. Statistical significance was determined using the non-parametric Spearman rho correlation analysis. RESULTS: After 120 min of reperfusion, recovery of LV work measured as developed pressure (DP)-heart rate (HR) product ranged from 0 to 15 ± 6.1 mmHg beats min(-1) 10(-3) following warm ischaemia of 15-25 min. Several haemodynamic parameters measured during early, unloaded perfusion at the time of heart procurement, including HR and the peak systolic pressure-HR product, correlated significantly with contractile recovery after cardioplegic storage and 120 min of reperfusion (P < 0.001). Coronary flow, oxygen consumption and lactate dehydrogenase release also correlated significantly with contractile recovery following cardioplegic storage and 120 min of reperfusion (P < 0.05). CONCLUSIONS: Haemodynamic and biochemical parameters measured at the time of organ procurement could serve as predictive indicators of contractile recovery. We believe that evaluation of graft suitability is feasible prior to transplantation with DCDD, and may, consequently, increase donor heart availability.

High acceptance rate of hybrid allogeneic-autologous umbilical cord blood banking among actual and potential Swiss donors

Two competitive concepts of umbilical cord blood (UCB) banking are currently available: either allogeneic UCB is donated to a public bank or autologous cells are stored in a private bank. Allogeneic-autologous hybrid banking is a new concept that combines these two approaches. However, acceptance of hybrid UCB banking among potential donors is unknown to date.

Intra-Arterial MSC Transplantation Restores Functional Capacity After Skeletal Muscle Trauma

Skeletal muscle trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Our group could show the efficacy of local transplantation of mesenchymal stroma cells (MSCs) for the treatment of injured muscles. While local application of MSCs has proven to be effective, we hypothesized that a selective intra-arterial transplantation would lead to a better distribution of the cells and so improved physiological recovery of muscle function.

Mechanical and radiological assessment of the influence of rhTGFbeta-3 on bone regeneration in a segmental defect in the ovine tibia: pilot study

Limitations in the use of autologous bone graft, which is the gold standard therapy in bone defect healing, drive the search for alternative treatments. In this study the influence of rhTGFbeta-3 on mechanical and radiological parameters of a healing bone defect in the sheep tibia was assessed. In the sheep, an 18-mm long osteoperiosteal defect in the tibia was treated by rhTGFbeta-3 seeded on a poly(L/DL-lactide) carrier (n = 4). In a second group (n = 4), the defect was treated by the carrier only, in a third group (n = 4) by autologous cancellous bone graft, and in a fourth group (n = 2) the defect remained blank. The healing process of the defect was assessed by weekly in vivo stiffness measurements and radiology as well as by quantitative computed tomographic assessment of bone mineral density (BMD) every 4 weeks. The duration of the experiment was 12 weeks under loading conditions. In the bone graft group, a marginally significant higher increase in stiffness was observed than in the PLA/rhTGFbeta-3 group (p = 0.06) and a significantly higher increase than in the PLA-only group (p = 0.03). The radiographic as well as the computed tomographic evaluation yielded significant differences between the groups (p = 0.03), indicating the bone graft treatment (bone/per area, 83%; BMD, 0.57 g/cm(3)) performing better than the PLA/rhTGFbeta-3 (38%; 0.23 g/cm(3)) and the PLA-only treatment (2.5%; 0.09 g/cm(3)), respectively. Regarding the mechanical and radiological parameters assessed in this study, we conclude that rhTGFbeta-3 has a promoting effect on bone regeneration. However, under the conditions of this study, this effect does not reach the potential of autologous cancellous bone graft transplantation.

Mechanisms of airway obliteration after lung transplantation

Post-transplant bronchiolitis obliterans, also called bronchiolitis obliterans syndrome, affects up to 50-60% of patients who survive 5 yr after surgery according to its clinical definition, which is based on the degree of obstructive airway disease. Alloimmune-independent and -dependent mechanisms produce injuries and inflammation of epithelial cells and subepithelial structures, leading to aberrant tissue repair. The triggering of innate immunity by various infections or chemical injuries after, for example, gastroesophageal reflux, may lead to the release of danger signals that are able to activate dendritic cells, a crucial link with adaptive immunity. Inflammation can also increase the expression and display of major histocompatibility alloantigens and thus favor the initiation of rejection episodes. These phenomena may be limited in time and location or may be protracted. Reducing the risk of alloimmune-independent factors may be as important as treating acute episodes of lung rejection. Excessive immunosuppression may be deleterious by increasing the risk of infection, thereby triggering innate and adaptive immunity. New potential therapeutic targets are emerging from the research performed on leukotriene receptors, chemokine receptors, and growth factors. Neutralizing these molecules reduces the initial mononuclear and polynuclear infiltrates or the subsequent fibroproliferative process and the neovascular changes, feeding this process.

ABO histo-blood group antigen expression on the graft endothelium long term after ABO-compatible, non-identical heart transplantation

We recently reported a complete change in the endothelial ABO histo-blood group phenotype of a cardiac allograft long term after B to O mismatched transplantation. In the context of the current controversy on graft recolonization with recipient endothelial cells and its importance in the development of immunological unresponsiveness, we monitored the expression of endothelial ABH histo-blood group antigens of 10 ABO-compatible, non-identical cardiac allografts over an observation period of at least 30 months. ABH antigens as well as markers for endothelial cells, erythrocytes and thrombocytes were investigated retrospectively by immunohistochemistry using monoclonal antibodies on sections of formalin-fixed, paraffin-embedded biopsies and were evaluated semi-quantitatively by microscopy. In contrast to our earlier finding of the change in the endothelial ABO histo-blood group phenotype long term after ABO- mismatched transplantation, we could not confirm this change in 10 compatible but non-identical cases.

Repair of superficial osteochondral defects with an autologous scaffold-free cartilage construct in a caprine model: implantation method and short-term results

OBJECTIVE: To compare four different implantation modalities for the repair of superficial osteochondral defects in a caprine model using autologous, scaffold-free, engineered cartilage constructs, and to describe the short-term outcome of successfully implanted constructs. METHODS: Scaffold-free, autologous cartilage constructs were implanted within superficial osteochondral defects created in the stifle joints of nine adult goats. The implants were distributed between four 6-mm-diameter superficial osteochondral defects created in the trochlea femoris and secured in the defect using a covering periosteal flap (PF) alone or in combination with adhesives (platelet-rich plasma (PRP) or fibrin), or using PRP alone. Eight weeks after implantation surgery, the animals were killed. The defect sites were excised and subjected to macroscopic and histopathologic analyses. RESULTS: At 8 weeks, implants that had been held in place exclusively with a PF were well integrated both laterally and basally. The repair tissue manifested an architecture similar to that of hyaline articular cartilage. However, most of the implants that had been glued in place in the absence of a PF were lost during the initial 4-week phase of restricted joint movement. The use of human fibrin glue (FG) led to massive cell infiltration of the subchondral bone. CONCLUSIONS: The implantation of autologous, scaffold-free, engineered cartilage constructs might best be performed beneath a PF without the use of tissue adhesives. Successfully implanted constructs showed hyaline-like characteristics in adult goats within 2 months. Long-term animal studies and pilot clinical trials are now needed to evaluate the efficacy of this treatment strategy.